|By Robert Cohen Executive Director|
= Autism & ADD
SCIENTIFIC PROOF: MILK CAUSES AUTISM & ADD
Florida researcher, Robert Cade, M.D., and his colleagues have identified a milk protein, casomorphin, as the probable cause of attention deficit disorder and autism. They found Beta-casomorphin-7 in high concentrations in the blood and urine of patients with either schizophrenia or autism.
(AUTISM, 1999, 3)
Eighty percent of cow's milk protein is casein. It has been documented that casein breaks down in the stomach to produce a peptide casomorphine, an opiate.
Another researcher observed that casomorphin aggravated the symptoms of autism.
(Panksepp, J. Trends in Neuroscience, 1979, 2)
A third scientist produced evidence of elevated levels of endorphin-like substances in the cerebro-spinal fluid of people with autism.
(Gillberg, C. (1988) Aspects of Autism: Biological
Research Gaskell:London, pp. 31-37)
The Autism Research Unit, School of Health Sciences has the following information on their website:
"The quantities of these compounds, as found in the urine, are much too large to be of central nervous system origin. The quantities are such that they can only have been derived from the incomplete breakdown of certain foods."
PARENT'S MAGAZINE REPORTS MILK LINK TO AUTISM
Search the Internet and you'll find many anecdotal stories from parents blaming their children's autism on milk and dairy products. One such story appeared in the February, 2000 issue of "Parent's Magazine."
See references 25 to 33 ____________________ A Chemical Aetiology for Autistic Spectrum Disorders: Opioid Peptides and Secretin Unpublished Paper by Stephen Dealler http://trainland.tripod.com/stephen.htm The suggestion that the syndrome of autism was similar in psychological terms to that seen in children who had received morphine was put forward by Panksepp in 1978 (1). The reason as to how this might take place in vivo when no morphine was being administered and no poppy derived products were present in their diet was initially unclear. The finding that casomorphins produced a reduction in distress by chicks when separated from others (2) was considered as evidence. Increased levels of a group of urinary peptides were found (3,4,5,6,7,8,9) and demonstrated by gel filtration, HPLC, and SDS-PAGE electrophoresis (10) These results were not found in the urine of children with the fragile X syndrome (4) and a different profile of peptide sizes was seen in late onset infantile autism, neonatal-onset infantile autism, and mixed onset cases including atypical ones (4). False-positive urinary profiles were found in 5-7% of controls and false negative ones in 5% (n=126) over 12 years. It has been known for some time that if peptidases are lacking in the gut then there is an increase in peptides found in the urine (11) but no histopathological changes have been reported in autism and no absolute lack of peptidases. It is suggested, however that the mechanism by which the peptides enter the blood is as a result of the lack of activity of two specific peptidases (4) as this fits with the genetic rate for the disease in siblings. There had been some indication of gut abnormality in that an excess of cases of coeliac disease was found (4) by one group and indications of malabsorption in others (12,13,14,15). Good research has shown that there is an abnormal intestinal permeability in children with autism (16) and hence the uptake of these peptides is not necessarily the result of the lack of specific peptidases at all. The hypotheses as to why opioid peptides should act to produce an autistic syndrome have been fully described in a chemical manner (6,17,18,19,20) but inadequate information is available to be certain of the mechanisms described. It was discovered that these individual peptides may have opioid activity (21,22,23) and certainly had biological activity of some kind (24). The finding that some had opioid-like receptor binding (24,25) was followed up by the finding that bovine casomorphins, opioid peptides from milk, were present in urine and dialysis fluid (4,25). It is known that casomophins and gluteomorphins are produced in the gut by proteinase digestion of milk and wheat proteins (26,27,28) and that casomorphins can have been involved in post partum psychosis (29) and hence penetrate the CNS (30). An increase in IgA antibodies was found in the blood of autistic children against gluten and casein (4) but in 4 of the 44 children no such antibodies were found whatever. This made the value of immune testing difficult to understand: there might have been a large enough absorption for the IgA to have interacted with the peptides and taken out of the circulation or only a small uptake; in which case antibodies were formed but are of little significance. When put onto a diet without milk or gluten-containing foods it can be shown that peptide excretion decreases in the urine from around 30mmol/24hrs to around 10mmol/24hrs (4,31) and when the diet was stopped the peptide excretion increased to previous levels. When first started on this diet, it was noted that some of the children showed a change in their psychological activity and were 'cold turkey' at some points over the first few days, suggesting an opioid withdrawal effect. Autistic patients put on a diet without gluten or milk protein improved clinically (4,5,31,32,33) and this was shown using psychological tests, tests of teaching, and indications by parents. Although it is difficult to explain the figures used to describe the improvement without understanding the mechanism, it is clear that an improvement did take place. A diet of this kind is difficult to maintain and a number of patients withdrew from the studies after having shown an improvement. These patients showed a slow regression to the previous condition (4) Autistic children (12) were tested with naltrexone, a long acting opiate inhibitor, in a double blind controlled trial and showed an overall improvement in their condition. The partial agonist activity of naltrexone was a problem in that higher doses appeared to have a lesser effect than lower ones (34). Also, the naltrexone did not alter the behaviour of the patient simply by decreasing all autistic action but rather by modifying certain ones. A reduction in stereotypies, increasing in verbal production, an improvement in social behaviour and self-injurious behaviour. Other, open trial studies, showed similar results (35-42). Overall the results were not as great as were hoped and when naltrexone was stopped, previous behaviour returned. It has been suggested that the long term exposure of the brain to peptide morphines from the diet would have a trophic effect on the brain in the same way as morphine itself (28,29,43) and that this may explain the progressive nature of autism in some cases; giving rise to an increase in epileptic fits and EEG abnormalities in increasing age (44). The long term endorphins and naltrexone were separately shown to modify the development of the brain (17,45). No research has been carried out currently to see what effect long term removal of these diet-derived peptides may have and whether any of the damage may recover. There have been individual reports of epilepsy ceasing following the removal of specific factors from the diet but the mechanisms are unclear. Secretin Secretin is a 27 amino acid polypeptide discovered in 1902 by Bayliss and Starling (46). Compared to other neuropeptides it has been poorly researched, with publications reaching a peak between 1980 and 1985 (47). Its aminoacid sequence was not found until 1965 (48) because of the low quantities that were present to test. However it was first synthesised shortly afterwards (49). The structure turned out to be well retained through evolution; both beef and porcine (50) secretin differed from human secretin by 2 amino acids and dog secretin differed by a single one (51). When formed in the rat it is made as a precursor protein intracellularly from a 739 base gene, of which only 692 bases are expressed as mRNA (52). The precursor protein exists as a signal peptide, an amino terminal peptide, secretin, and a carboxy terminal peptide. The signal, amino and carboxy terminal peptides are cleaved from secretin before its release. This precursor and gene are identical in the duodenum and in the brain. Secretin is one of a group of neuropeptides that were originally felt to be found only in the gut and to act as endocrines. All of them have been found to be present in the brain also. They are known as the secretin group of peptides (table 1). This is important as research into all of these has been greater than into secretin itself (7) and certain factors from this research are expected to be significant for secretin. This group of neuropeptides is remarkable in that, although they are similar in structure, they have often quite different activities and different receptors in tissues. Some of them will cross react between receptors but the cross reaction is minimal in vivo despite this similarity (52a). It is likely that evolutionary change has demanded specific action even as a result of small changes in the peptide structure. As a result it would be expected that only small changes in secretin structure would decrease its activity but possibly not alter its assay using standard radio-immunoassay techniques. Because of this it is essential that if any assay of secretin is undertaken, it is necessary to test the activity of the hormone and its structure: not just the presence of the peptide. Secretin mode of action Secretin interacts with highly specific cellular surface receptors which carry intracellularly a Gs type protein which then changes the action of certain cellular enzymes. Human secretin receptors belong to a seven- transmembrane domain subfamily that includes receptors for VIP, PACAP and glucagon. The receptor structures have been well worked out (53) as being generally around 1616 bases (54) in length (53) and distinct receptors were characterized in the guinea pig pancreatic acini (54), rat gastric glands (55), rat cholangiocytes (56), mouse neuroblastoma cells (57), and mouse-rat NG108-15 neuroblastoma-glioma hybrid cells (58). The rat secretin receptor (RSR) cDNA was the first to be worked out as a member of a distinct new family of G protein-coupled receptors (59) that now include VIP (60,61,62), PACAP (63,64,65), glucagon (66,67), parathyroid hormone (68) and calcitonin (69). It can be shown that rat and human receptors are similar; being closely homologous except at the amino and carboxy terminals (53). The main action seen is the increase in adenyl cyclase activity and it is thought that this is the major mode of action of secretin both in the periphery and in the central nervous system. There is also an increase in calcium inside the affected cell and an increase in inositol phosphate production. A modified form of secretin has been shown to act as an antagonist in vivo in rodents due to its ability to interact with the receptor but in some way not stimulate its activity (49) Secretin activity in the periphery Secretin is only produced peripherally by the S cells of the proximal section of the duodenum and acts as a feed back loop used to counter the stomach acid arriving there after food. The presence of acidic fluid in the duodenum or the distension of it causes secretin release. This is passed though the circulation to acinar cells of the pancreas where it causes an increase in the release of alkali. It causes an increase in fluid release from the biliary system, the small intestine epithelium and the pancreas. It decreases the production of gastric acid, gastrin (69), but increases the release of pepsinogen from gastric chief cells. Some cardiac and renal activity is seen but this has not been fully investigated. Secretin also causes an increase in the activity of tyrosine hydroxylase (TH) in cervical ganglion neurones and phaeochromocytoma cells (70,71). This enzyme is the limiting section of the manufacture of catecholamines (e.g. adrenaline) and hence it is felt that some adrenergic activity may be seen as a result but it has not been quantified. TH activity has been shown to be subject to the regulation by the cAMP system inside the cell as well as calcium and cGMP second messenger systems (70). Treatment of intact rat PC12 cells with neuropeptides including secretin stimulated TH activity 2 to 3 fold (71). This activity is not surprising in that receptors for secretin have been found to be present in the pancreas, kidney, rat gastric glands, cholangiocytes, neuroblastoma cells, neuroblastoma glioma cells, lung, and intestinal epithelium. All of these appear to have more receptor activity than that seen in brain, heart or ovary. However no receptors at all are seen in other tissues tested. Cross reactivity between the secretin group peptides has been seen but to a low degree. Measured KD levels were 10-7 to 10-10 mol. In neonatal animal experimental secretin has been shown to be involved in the growth and development of the gut, stomach and pancreas (72,73). Secretin activity in the brain The quantity of secretin in neurological tissues seems to be similar to that in the duodenum, varying between 7pg/mg (wet weight) of the cortex to 130 pg/mg of the pineal (74) (table 2). It was first demonstrated in the brain of the rat and pig (but not in the guinea pig)(75). Highest levels were found in the medulla oblongada, thalamus, hypothalamus olfactory bulb, hippocampus, midbrain, cerebellum and brain stem (74,80) Initially there was difficulty in demonstrating that this was correct and researchers failed to repeat the findings. However the demonstration of mRNA for the precursor peptide in similar quantities to that found in the duodenum in the same tissue ratios as found for the secretin itself means that this can no longer be open to argument. Like other transmitters such as dopamine, the action of peptides may be through the stimulation of adenylate cyclase thus increasing levels of cyclic AMP to cause intracellular changes rather than alterations in transmembrane potentials (70,76,77) as is seen with acetyl choline. Specific activity has been shown by secretin: inhibition of prolactin and leutinising hormone release; displacement of VIP from certain receptors; increase the turnover and level of dopamine; increase in adenyl cyclase activity in the hypothalamus; glycogenolysis in primary culture glial cells; enhancement of pancreatic volume and bicarbonate response to acid in the duodenum (this was shown not to be a systemic effect of secretin escaping from the intracerebral inoculation of the drug into the blood) (78) Penetration of the blood brain barrier One of the major questions in this field has been whether or not secretin and other neuropeptides could be used as therapeutic agents. Around 50% that have been tested have been found to cross the blood brain barrier easily and rapidly with levels appearing in the CSF within 5 minutes of peripheral inoculation (79). Secretin has not been tested in this respect but, as all of the other members of the group seem to penetrate the BBB, it is unlikely that it is not true for secretin (80). The finding that i.v. secretin caused a rapid increase in prolactin whereas i.c. it caused a decrease, has suggested that there is a short negative feed back loop present and that this probably is taking place in the hypothalamus. This also suggests that the BBB is penetrated by secretin and reaches some specifically sensitive site. Further work must be carried out into this, however. It should also be remembered that intraventricularly administered peptides also appear rapidly in the blood (81) although, again this experiment was not carried out with secretin. Lack of secretin activity as a potential cause of the gut uptake and inadequate breakdown of opioid peptides in autistics The genetic aspects of autism suggest that either two gene abnormalities are required or, as there is a 36%-91% correalation in monozygotic twins (82,83,84) it would suggest an approximately 50% penetration of a single gene. The finding of a dizygotic sibling concordance rate of 3% is similar to that seen in a condition that required two recessive alterations (6.3%), rather than the 50% penetration of a single one, which would appear in 12.5%. The finding that the gut in autistics may be abnormal in that it takes up long chain molecules (16), may suggest that it is not so much the peptidase acitivity that is inadequate but that there is a physiological barrier between the gut and the blood that is ineffective. This has been shown with carbohydrates and with peptides. It has been shown that secretin is relatively high in the blood of neonates (72,73) and that infusions of it causes precocious cessation of intestinal macromolecular transmission (72). The clinical effect seen from secretin in autism is strange in that the action has been reported as descriptions from patients' relatives to increase for several days after a single intravenous injection and the effect is seen to reach a peak between 2 and 4 weeks. This cannot be simply due to the effect of secretin on the brain as a neurotransmitter as the half-life of compound is short. This long term effects suggested would fit better with secretin as an inducer of protein production or cellular maturation. causing an alteration in cells that would either be themselves destroyed or lose the action gradually. Although secretin when inoculated intrecerebrally was shown to induce morphine action, this effect did not last for long periods and hence cannot be thought of as the specific cause of the phenomenon in autism (85). For instance, one hypothesis could be that the action of the injected secretin may be as an inducer of changes in the gut epithelium cells that are themselves lost by shedding over the following weeks. If secretin was seen to prevent the pathological gut physiology seen in some autistic children then this effect might be seen if inadequate secretin was being produced by the S cells of the duodenum or if the secretin that was produced did not interact adequately with the receptor molecules (this might be found if only small changes were made). Some autistic cases may not respond at all to secretin and either the mechanism by which it would act was faulty (e.g. the secretin receptors) or some other pathology was present to which secretin was not significant. Also, it must be remembered that alterations in the receptor may give rise to inadequate action taking place on the G- protein and from there a lack of change in cellular adenyl cyclase activity. If this chain of action gave rise to the lack of secretin physiology in the autistic child, then it would not be found that all would respond to injected hormone. Only those in which the secretin was missing or altered would improve. Any cases in which it was either the receptor or its mode of action that were ineffective would not respond. Psychology It may also be worth discussing how, in psychological terms, disruptions of opioid mechanisms might lead to the symptoms of autism. There is convincing evidence that autistic spectrum disorders are associated with what are termed theory-of-mind problems (86, 87, 89). This means that autistic children appear unable to comprehend the mental states of other people or appreciate their perspectives. This specific pattern of psychological problems is associated with other, still quite specific, problems with what is termed central executive functioning (90,88). A convincing argument can be developed to the conclusion that specific deficits in central executive functioning, probably the ability simultaneously to process more than two pieces of information, lead to the problems observed in autistic spectrum disorders. It is entirely possible that secretin and other opioid peptides mediate these processes. Discussion The reports that secretin appears to improve a group of autistic children and that this takes place over a period much greater than it would be expected due to its short term action as a neurotransmitter and to induce the release of alkali into the duodenum. The long term hormonal action of secretin has been poorly investigated but may involve gut development. The finding that secretin inoculated into 3 autistic children (91) caused an excessively large increase in alkali secretion would be consistent with there being inadequate secretin present normally. While the long term hormonal actions of secretin are inadequately studied, further research needs to be carried out concerning autism; first to see if secretin has adequate action in autism at all (92) but if it does, however small, to follow its mode of action as a key to the physical and chemical pathology of the condition as yet poorly understood. 92 References: 1. Panksepp J, Normansell L, Siviy St, Diruibe VA, Abbou-Issa H. Potential biochemical markers for infantile autism. Neurochem Pathol 1986;5:51-70. 2. Panksepp. A neurochemical theory of autism. Trends Neurosci 19789;2:174-177. 3. Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD, Braestrup CB, Lingjaerde O, Ledaal P, Orbeck H. Biologically active peptide-containing fractions in schizophrenia and childhood autism. Neurosecretion and Brain Peptides. Ed: JB Martin, S. Reichlin and KL Bick. Raven Press, New York 1981. 627-643 4. Reichelt KL, Knivsberg AM, Lind G, Nodland M. Probable etiology and possible treatment of childhood autism. Brain dysfunct 1991;4:308-319. 5. Reichelt KL, Knivsberg AM, Nodland M, Lind G. Nature and consequences of hyperpeptiduria and bovine casomorphins found in autistic syndrome. Dev Brain Dysfunction 1994;7:71-85. 6. Shattock P, Kennedy A, Rowell F, Berney T. Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunction 1990;3:328-345. 7. Shattock P, Savery D. Evaluation of urinary profiles obtained from people with autism and associated disorders. Part 1: Classification of subgroups. In: Proceedings of conference on Living and Learning with Autism: Perspectives from the Individual, the Family and the Professional, April 1997 199-208. 8. Shattock P, Savery D. Urinary profiles of people with autism: Possible implications and relevance to other research. In: Procedings of Conference on Therapeutic Interventions in Autism: Perspectives from Research and Practice. April 1996 309-325. 9. Gilberg C, Trygstad O, Fossi I. Childhood psychosis and urinary exretion of peptides and protein-associated peptide complexes. J Autism Dev Disord 1982;12:229-41. 10. Williams K, Shattock P, Berney T. Proteins, peptides and autism. Part 1: Urinary protein patterns in autism as revealed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and silver staining.Brain dysfunction 1991;4:320-322. 11. Mahe S, Tome D, Dumontier AM, Deseux JF. Absorption of intact morphiceptin by diisopropyl fluorophosphate-treated rabbit ileum. Peptides 1989;10:45-52. 12. Coleman M. Calcium studies and their relationship to coeliac disease in autistic patients. In: Colerman M (ed). Autistic Syndromes. Amsterdam North Holland Press. 1976. 197-205. 13. Goodwin MS, Cowen MA, Goodwin TC. Malabsorption and cerebral dysfunction. A multivariate and comparative study of autistic children. J Autism Child Schizophr 1971;1:48-62. 14. Shattock P. Autism: Possible clues to the underlying pathology. A parent's view: in: Wing L (ed) Aspects of Autism. Biological Research. London, Gaskell 1988, 11-18. 15. Fung BP, Rongo A, Leiter AB. Genetic ablation of secretin cells in transgenic mice reveals lineage relationsips between multiple endocrine cell types in the small intestine. Gastroenterology AGA Abstracts 1994;110(4):A1112. 16. D'Eufemia P, Celli M, Finocchiaro R, Pacifico L, Viozzi L, Zaccagnini M, Cardi E, Giardini O. Abnormal intestinal permeability in children with autism. Acta Paeiatrica 1996;85:1076-9. 17. Shattock P, Lowdon G. Proteins, peptides and autism. Part 2. Implications for the education and care of people with autism. Brain Dysfunction 1991;4:323-334. 18. Gillberg C. The role of endogenous opioids in autism and the possible relationships to clinical features. In: Wing L (ed) Aspects of Autism: Biological Research. London, Gaskell, 1988, 31-37. 19. Reichelt KL, Scott H, Knivsberg AM, Wiig K, Lind G, Nodland M. Childhood autism: A group of hyperpeptidergic disorders. Possible etiology and tentative treatment: In Nyberg F, Brantl V (eds) Beta=Casomorphins and Related Peptides. Uppsala, Eyris-Tryck AB, 1990, 163-173. 20. Gillberg C. Theoretical considerations: CNS mechanisms underlying the autistic syndrome. In Coleman M, Gillberg C (eds) The Biology of the Autistic Syndromes. New York, Praeger, 1985 197-206. 21. Reichelt KL, Saelid G, Lindback T, Boler JB. Childhood autism: A complex disorder. Biol Psychiatry 1986;21:1279-1290. 22. Shattock P. Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunction 1990;3:328-346. 23. Israngkun PP, Newman HA, Patel ST, Duruibe VA, Abou-Issa H. Potential biochemical markers for infantile autism. Neurochem Pathol 1986;5:51-70. 24. Reichelt KL, Knivsberg AM, Nodland M, Pedersen OS. Correlation of found bioactivities with symptoms typical of autistic syndromes. In Proceedings of conference on Biological Perspectives in Autism. April 1993 65-83. 25. Reichelt KL, Knivsberg AM, Nodland M, Lind G. Nature and consequence of hyperpeptiduria and bovine casomorphine found in autistic syndromes. Brain Dysfunction 1994;7:71-85. 26. Zioudrou C, Streaty RA, Klee WA. Opioid peptides derived from food proteins. J Biol Chem 1979;254:2446-9. 27. Swedberg J, de Haas J, Leimanstoll G, Paul F, Teschemacher H. Demonstration of beta-casomorphin immunoreactive materials in vitro digests of bovine milk and in small intestine contents after bovine milk ingestion in adult humans. Peptides 1985;6:825-831. 28. Umbach H, Teschemacher H, Praetorius K, Hirschhauser R, Bostedt H. Demonstration of beta-casomorphin immunoreactive material in the plasma of newborn calves after milk intake. Regul Pept 1985;12:223-230. 29. Linstrom LH, Nyberg F, Terenius L, Bauer K, Besev G, Gunne LM, Lyrens S, Willdeck-Lund GJ, Lundberg B. CSF and plasma beta-casomorphin-like opioid peptides in post-partum psychosis. Am J Psychiatry 1984;141:1059-66. 30. Hemmings WA. The entry into the brain of large molecules derived from dietary protein. Proc R Soc Lond (Biol) 1978;200:175-192. 31. Whiteley P, Rodgers J, Savery D, Shattock P. A gluten-free diet as an intervention for autism and associated spectrum disorders: Preliminary findings. Autism 1999;3:45-65. 32. Knivsberg AM, Wiig K, Lind G, Nodland M, Reichelt KL. Deitary intervention in autistic syndromes. Brain Dysfunction 1990;3:315-327. 33. Knivsberg AM, Reichelt KA, Nodland M, Hoien T. Autistic syndromes and diet: a follow-up study. Scandinavian Journal of Educational Research 1995;39:223-236. 34. Scifo R, Batticane N, Quattropani MC, Spoto G, Marchetti B. A double-blind trial with naltrexone in autism. Brain Dysfunction 1991;4:301-307. 35. Herman BH, Hammock MK, Arthur-Smith A, Egan J, Chatoor I, Werner A, Zelnick N. Naltrexone decreases self-injurous behaviour. Ann Neurol 1987;22:550-552. 36. Lensing PJ. Two single studies with naltrexone. Acts Conf: Experimental Psychology and The Austistic Syndromes, Durham, 1990 67-93. 37. Leboyer M, Bouvard M, Dugas M. Effects of naltrexone in infantile autism. Lancet 1988;i:715. 38. Leboyer M, Bouvard M, Lensing P, Launa JM, Tabuteau F, Waller D, Plumet MH, Recasens C, Kerdelhue B, Dugas M, Panksepp J. The opiod excess hypothesis of autism: A double blind study of naltrexone. Brain Dysfunction 1990;3:285-298. 39. Campbell M, Overall JE, Small A, Sokol MS, Spencer E, Adams P, Foltz R, Monti K, Perry R, Nobler M, Roberts E. Naltrexone in autistic children: An acute open dose range tolerance trial. J Am Acad Child Adolesc Psychiatry 1989;28:200-206. 40. Lensing PJ, Klinger D, Gerstl W, Panksepp J. Clinical notes on naltrexone therapy for five autistic children. Provisional guidelines for future research. Acts Conf: Experimental Psychology and The Autistic Syndromes, Durham 1989 219-232. 41. Campbell M, Perry R, Small A, McVeigh-Tesch L, Curren E. Naltrexone in infantile autism. Psychopharmacol Bull 1988;24:135-139. 42. Panksepp J, Lensing P, Leboyer M, Bouvard MP. Naltrexone and other potential new pharmacological treatments of autism. Brain Dysfunction 1991;4:281-300. 43. Zagon IS, McLaughlin PJ. Endogenous opioid systems regulate cell proliferation in the developing rat brain . Brain re 1987;412:68-72 44. Deykin EY, Macmhon N. The incidence of seizures among children with autistic syndromes. Am J Psychiatry 1979;136:1310-12. 45. Shattock P, Kennedy A, Rowell F, Berney T. Role of neuropeptides in autism and their relationships with classical neurotransmitters. Brain Dysfunction 1990;3:328-334. 46. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J. Physiol (London) 1902;28:325-53. 47. Myers RD. Neuroactive peptides: Unique phases in research on mammalian brain over three decades. Peptides 1994;15:367-381. 48. Mutt V, Magnussion S, Jorpes JE. Structure of porcine secretin. 1. Degradation with trypsin and thrombin. Sequence of the tryptic peptides. The C-terminal residue. Biochemistry 1965;4:2358-67. 49. Bodanszky M, Ondetti MA, Levine SP, Williams NJ. Synthesis of secretin. II The stepwise approach. J Am chem Soc 1964;89:6753-6757. 50. Nishitani J, Lopez MJ, Leiter AB. Transcriptional regulation of secretin gene expression. J Clin gastroenterol 1995;21(suppliment 1):S50-55. 51. Shinomura V, Eng J, Yalow RS. Dog secretin: sequence and biological activity. Life Sciences 1987;41:1243-48. 52. Itoh N, Furaya T, Ozaki K, Ohta M, Kawasaki T. The secretin precursor gene. J Biol Chem. 1991;266:12595-12598. 52a Chieweiss H, Glowinski J, Premont J. Do secretin and vasoactive intestinal peptide have independent receptors on striatal neurons and glial cells in primary cultures? Journal of Neurochemistry 1986;47:608-613. 53. Patel DR, Kong Y, Sreedharan P. Molecular cloning and expression of a human secretin receptor. Molecular Pharmacology 1995;47:467-73. 54. Haffar BM, Hocart SJ, Coy DH, Mantey S, Chiang HV, Jensen RT. Reduced peptide bond pseudopeptide analogues of secretin: a new class of secretin receptor antagonists. J. Biol. chem. 1991;266:322. 55. Bawab W, Gespach C, Marie JC, Chastre E, Rosselin G. Pharmacology and molecular identification of secretin receptors in rat gastric glands. Life Sci. 1988;42:791-798. 56. Kato A, Gores GJ, LaRusso NF. Secretin stimulates exocytosis in isolated bile duct epithelial cells by a cyclic AMP mediated mechanism. J Biol Chem. 1992;267:15523-15529. 57. Roth BL, Beinfeld MC, Howlett AC. Secretin receptors on neuroblastoma cell membranes:characterization of 125I-labelled secretin binding and association with adenylate cyclase. J Neurochem. 1984;42:1145-1152. 58. Gossen D, Tastenoy M, Robberecht P, Christophe J. Secretin receptors in the neuroglioma hybrid cell line NG108-15: characterization and regulation of their expression. Eur J Biochem 1990;193:149-154. 59. Ishihara T, Nakamura S, Kaziro Y, Takahashi T, Takahashi K, Nagata S. Molecular cloning and expression of a cDNA encoding the secretin receptor. EMBO J 1991;10:1635-41. 60. Sreedharan SP, patel DR, Huang J, Goetzl EJ. Cloning and functional expression of a human neuroendocrine vasoactive intestinal peptide receptor. Biochem Biophys Res Commun 1993;193:546-553. 61. Lutz EM, Sheward WJ, West KM, Morrow JA, Fink G, Harmar AJ. The VIP(2) receptor: molecular characterization of a cDNA encoding a novbel receptor for VIP. FEBS Lett 1993:334:3-8. 62. Inagaki N, Yoshida H, Mizuta M, Mizuno N, Fujii Y, Gonoi T, Miyazaki J, Seino S. Cloning and functional characterisation of a third PACAP receptor subtype expressed in insulin-secreting cells. Proc Natl Acad Sci USA 1994;91:2679-2683. 63. Pisegna JR, Wank SA. Molecular cloning and functional expression of the PACA: type I receptor. Proc Natl Acad Sci USA 1993;90:6345-6349. 64. Hashimoto H, Ishihara T, Shigemoto R, Mori K, Nagata S. Molecular cloning and tissue distribution of a receptor for PACAP. Neuron 1993;11:333-342. 65. Spengler D, Waeber C, Pantaloni C, Holsboer F, Bockaert J, Seeburg PH, Journot L. Differential signal transduction by five splice variants of the PACAP receptor. Nature (London) 1993;365:170-175. 66. Jelenek LJ, Lok S, Rosenburg GB et al. Expression cloning and signalling properties of the rat glucagon receptor. Science (Washington DC) 1991;254:1024-1026. 67. MacNeil DJ, Occi JL, Hey PJ, Strader CD, Graziano MP. Cloning and expression of a human glucagon receptor. Biochem Biophys Res Commun 1994;198:328-334. 68. Juppner JA, Abou-Samra AB, Freeman M, Kong X, Shipani E, Kolakowski LF, Hock J, Potts JT, Kronenberg HM, Segre GV. A G-protein linked receptor for parathyroid homone and parathyroid homone-related peptide. Science (Washington DC) 1991;254:1024-1026. 69. Lin HY, Harris TL, Flannery MS, Aruffo A, Kaji EH, Gorn A, Kolakowski LF, Lodish H, Goldring SR. Expression ofan adenylate-cyclase-coupled calcitonin receptor. Science (Washington DC) 1991;254:1022-1024. 70. Fremeau RT, Korman LY, Moody TW. Secretin stimulates cyclic AMP formation in the rat brain. J Neurochem 1986;46:1947-55. 71. Roskoski R, White L, Knowlton R, Roskoski LR. Regulation of tyrosine hydroxylase activity in rat PC12 cells by neuropeptides of the secretin family. Pharmacology 1989;36:925-931. 72. Harada E, Syuto B. Secretin induces precocious cessation of intestinal macromolecular transmission and maltase development in the suckling rat. Biol neonate 1993;63:52-60. 73. Pollack PF, Wood JG, Solomon T. Effect of secretin on growth of stomach, small intestine, and pancreas of developing rats. digestive Diseases and Sciences 1990;35:749-58. 74. Samson WK, Lumpkin MD, McCann SM. Presence and possible site of action of secretin in the rat pituitary and hypothalamus. Life Sciences 1984;34:155-163. 75. O'Donohue TL, Charlton CG, Miller RL, Boden G, Jacobowitz DM. Identification, characterization and distribution of secretin immunoreactivity in rat and pig brain. Proc Natl Acad Sci USA 1981;78:5221-4. 76. Chneiweiss H, Glowinski J, Pridont J. Vasoactive intestinal po;ypeptide receptors linked to an adenylate cyclase, and their relationship with biogenic amine- and somatostatin-sensitive adenylate cyclases on central neuronal and glial cells in primary cultures. J neurochem 1985;779-786. 77. Van Calker D, Muller M, Hamprecht B. Regulation of secretin, vasoactive intestinal peptide and somatostatin of cyclic AMP accumulation in cultures brain cells. Proc Natl Acad Sci USA 1980;77:6907-11. 78. Conter RL, Hughes MT, Kauffman GL. Intracerebroventricular secretin enhances pancreatic volume and bicarbonate response in rats. Surgery 1996;119:208-213. 79. Banks WA, Kastin AJ. Peptide transport systems for opiates across the blood-brain barrier. Am J Physiol 1990;259:E1-10. 80. Banks WA, Kastin AJ, Garzone PD, Colburn WA, Mokotoff M. Eds. Regulation of the passage ofpeptides across the bloo-brain barrier. In Pharmacokinetics and Pharmacodynamics, Vol 3. Peptides, Peptoids, and Proteins. Harvey Whitney Books. Cincinnati. 1991 147-153. 81. Passaro EP, Debas H, Oldendorf W, Yamada T. Rapid appearance of intraventricularly administered neuropeptides in the peripheral circulation. Brain Res 1982;241:335-340. 82. Folstein S, Rutter M. Infantile autism: A genetic study of 21 twin pairs. J Child Psychol Psychiatry 1977;18:297-331. 83. Steffenburg S, Gillberg C, Hellgren L, Andersson L, Gillberg I, Jakobsson G, Bohman M. A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden. J Child Psychol Psychiatry 1989;30:405-416. 84. Smalley S, Asarmow R, Spence M. Autism and genetics: A decade of reseearch. Arch Gen Psychiatry 1988;45:953-961. 85. Babarczy E, Szabo G, Telegdy G. Effect of secretin on acute and chronic effects of morphine. Pharmacology Biochemistry and Behaviour 1995;51:469-72. 86. Baron-Cohen, S. (1995). Mindblindness: An essay on autism and theory of mind. Cambridge, Mass.: MIT Press. 87. Happé, F., 1:9-15. 92. Owley T, Steel E, Corsello C et al. A dougle blind, placebo-controlled trial of secretin for the treatment of autism. Medscape General Medicine 6th October 1999.
For children with autism, milk may very well be
the major factor. One out of five American
children have been diagnosed with attention
deficit disorder. One out of five American children
take Ritalin. An alternative therapy? NOTMILK!
Robert Cohen author of: MILK A-Z
Executive Director (email@example.com)
Dairy Education Board
Do you know of a friend or family member with one or more of these milk-related problems? Do them a huge favor and forward the URL or this entire file to them.
Do you know of someone who should read these newsletters? If so, have them send an empty Email to firstname.lastname@example.org and they will receive it (automatically)!